Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species.
OBJECTIVE
We have previously reported that matrix metalloproteinases MMP-2, MMP-9, and the complex MMP-9/NGAL can be detected in urine of patients with a variety of cancers including prostate and bladder carcinoma. In addition, we also detected several unidentified urinary gelatinase activities with molecular weights >125 kDa. The objective of the current study was to identify these high molecular weight (HMW) species, determine their potential as predictors of disease status, and ask whether a tumor-specific pattern existed based on urinary MMP analysis.


METHODS
Chromatography, zymography, and mass spectrometry was used to identify HMW gelatinase species of approximately 140, 190, and >220 kDa in urine of cancer patients. To determine whether a tumor-specific pattern of appearance existed among the MMPs detected, we analyzed the urine of 189 patients with prostate or bladder cancer and controls.


RESULTS
The approximately 140, >220 kDa, and approximately 190 HMW gelatinase species were identified as MMP-9/tissue inhibitor of metalloproteinase 1 complex, MMP-9 dimer, and ADAMTS-7, respectively. The frequency of detection of any MMP species was significantly higher in urine from prostate and bladder cancer groups than controls. MMP-9 dimer and MMP-9 were independent predictors for distinguishing between patients with prostate and bladder cancer (P < 0.001 for each) by multivariable analysis.


CONCLUSIONS
This study is the first to identify a tumor-specific urinary MMP fingerprint that may noninvasively facilitate identification of cancer presence and type. This information may be of diagnostic and prognostic value in the detection and/or clinical monitoring of disease progression and therapeutic efficacy in patients with bladder or prostate cancer.
Roy
Roopali
R
Department of Surgery, Children's Hospital, Boston, MA 02115, USA.
Louis
Gwendolyn
G
Loughlin
Kevin R
KR
Wiederschain
Dmitri
D
Kilroy
Susan M
SM
Lamb
Carolyn C
CC
Zurakowski
David
D
Moses
Marsha A
MA
D051722:ADAM Proteins / Q000652:urine; D000071118:ADAMTS7 Protein; D014408:Biomarkers, Tumor / Q000652:urine*; D016022:Case-Control Studies; D019281:Dimerization; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000652:urine*; D020780:Matrix Metalloproteinase 9 / Q000652:urine*; D008970:Molecular Weight; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000652:urine; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000652:urine; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000652:urine
D014408:Biomarkers, Tumor; D019715:Tissue Inhibitor of Metalloproteinase-1; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C121534:ADAMTS7 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9